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SPECIAL ARTICLE
Bleeding in acute coronary syndromes and
percutaneous coronary interventions: position
paper by the Working Group on Thrombosis of
the European Society of Cardiology
Philippe Gabriel Steg (France)*, Kurt Huber (Austria), Felicita Andreotti (Italy),
Harald Arnesen (Norway), Dan Atar (Norway), Lina Badimon (Spain),
Jean-Pierre Bassand (France), Raffaele De Caterina (Italy),
John A. Eikelboom (Canada), Dietrich Gulba (Germany), Martial Hamon (France),
Ge
´rard Helft (France), Keith A.A. Fox (UK), Steen D. Kristensen (Denmark),
Sunil V. Rao (USA), Freek W. A. Verheugt (Netherlands),
Petr Widimsky
´(Czech Republic), Uwe Zeymer (Germany), and
Jean-Philippe Collet (France)
Received 15 February 2011; revised 27 March 2011; accepted 27 May 2011
Bleeding has recently emerged as an important outcome in the management of acute coronary syndromes (ACS), which is relatively frequent
compared with ischaemic outcomes and has important implications in terms of prognosis, outcomes, and costs. In particular, there is evi-
dence that patients experiencing major bleeding in the acute phase are at higher risk for death in the following months, although the causal
nature of this relation is still debated. This position paper aims to summarize current knowledge regarding the epidemiology of bleeding in
ACS and percutaneous coronary intervention, including measurement and definitions of bleeding, with emphasis on the recent consensus
Bleeding Academic Research Consortium (BARC) definitions. It also provides an European perspective on management strategies to mini-
mize the rate, extent, and consequences of bleeding. Finally, the research implications of bleeding (measuring and reporting bleeding in trials,
the importance of bleeding as an outcome measure, and bleeding as a subject for future research) are also discussed.
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Keywords Bleeding †Haemorrhage †Percutaneous coronary intervention †Thrombosis †Acute coronary syndromes †
Unstable angina †Myocardial infarction
Rationale
Enormous strides have been made in improving the care of
patients with acute coronary syndromes (ACS), resulting in sub-
stantial improvements in acute outcomes.
1
Among these develop-
ments, key factors appear to be steady refinements in
antithrombotic therapy in the acute phase, which nowadays routi-
nely includes oral antiplatelet drugs (aspirin and thienopyridines), a
parenteral antithrombin [unfractionated heparin (UFH),
low-molecular-weight heparins, fondaparinux, or bivalirudin]
given intravenously or subcutaneously, and often an intravenous
glycoprotein IIb/IIIa receptor blocker. In addition, the early use of
coronary angiography with a view to revascularization has
increased and has often become the default management
approach. As the efficacy of treatment increased, the residual
risk of major adverse cardiac events related to thrombosis, such
as death and myocardial infarction, diminished, and the potential
for further improvement in efficacy declined. Renewed attention
*Corresponding author. INSERM U-698, Universite
´Paris-Diderot and Centre Hospitalier Bichat, Assistance Publique-Ho
ˆpitaux de Paris, 46 rue Henri Huchard, 75018 Paris, France.
Tel: +33 1 4025 8668, Fax: +33 1 40 25 88 65, Email: gabriel.steg@bch.aphp.fr
Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2011. For permissions please email: journals.permissions@oup.com
European Heart Journal
doi:10.1093/eurheartj/ehr204
European Heart Journal Advance Access published June 29, 2011
at REDAR on June 30, 2011eurheartj.oxfordjournals.orgDownloaded from
has therefore been drawn to the other side of the risk/benefit
equation: bleeding. This article aims to summarize current knowl-
edge regarding bleeding in ACS and percutaneous coronary inter-
vention (PCI), including the epidemiological evidence, basic
research issues, and an European perspective on management
strategies to minimize the rate and extent of bleeding. In addition,
a recent unified effort from stakeholders involved in studies of
antithrombotic agents led to a consensus bleeding definition, the
Bleeding Academic Research Consortium (BARC), which is
presented.
Bleeding definitions
The overall aim of classifications is to systematize the reporting and
categorization of bleeding events in a numerical and unequivocal
fashion to allow comparisons across data sets. Some of the most
widely used bleeding definitions used in clinical trials are the cri-
teria developed by the ‘Thrombolysis in Myocardial Infarction’
(TIMI)
2
and the ‘Global Use of Strategies To Open coronary
arteries’ (GUSTO) study groups
3
(Table 1). The latter are clinically
based, while the former definition includes laboratory-based
assessments. Many other definitions are used. All have been
refined over time to attempt to be as objective as possible and
account for blood transfusions, yet the prognostic impact of bleed-
ing may vary across definitions.
4
Used originally for the study of thrombolytic regimens in acute
myocardial infarction, these classifications have subsequently been
used in many PCI studies, although they may fail to capture bleed-
ing which is clinically relevant in that setting, such as bleeding at
vascular access sites.
5
Conversely, many ACS studies have devel-
oped their own scales,
4,6,7
and have sometimes enrolled patients
undergoing either conservative (medical) treatment or PCI, with
no particular differentiation between non-invasive or invasive
treatment algorithms (Table 1). The International Society on
Thrombosis and Haemostasis (ISTH) has proposed a bleeding
scale to increase comparability across studies,
8
which was
endorsed by the European Medicines Agency (EMA),
9
with the
recommendation, however, of adding the ‘cessation’ criterion. In
addition to these criteria, the Agency demands meticulous record-
ing of haemoglobin (Hb) and haematocrit (Hc) changes, as well as a
quantification of blood loss by an objective method.
While most classifications have evolved towards increased
reporting details, other scales have attempted a simplification of
reporting, as in the classification by the Global Registry of Acute
Coronary Events (GRACE) Investigators.
10
Others have argued
for an increased focus on minor long-term bleeding events,
11
often either neglected or under-reported in trials, but which may
be of importance to patients beyond the acute phase and impact
adherence to antithrombotic therapies
12
proposing a bleeding
classification that covers the entire spectrum of bleeding
...............................................................................................................................................................................
Table 1 Examples of frequently used classifications of bleeding events
2,3,6–8
Classification Severity Criteria
TIMI Major Intracranial bleeding. Overt bleeding with a decrease in haemoglobin ≥5 g/dL or decrease in haematocrit
≥15%
Minor Spontaneous gross haematuria. Spontaneous haematemesis. Observed bleeding with decrease in
haemoglobin ≥3 g/dL but haematocrit ≤15%
Insignificant Blood loss insufficient to meet criteria listed above
GUSTO Severe Deadly bleeding. Intracerebral bleeding or substantial haemodynamic compromise requiring treatment
Moderate Bleeding requiring transfusion
Mild Other bleeding not requiring transfusion or causing haemodynamic compromise
ACUITY Major Intracranial or intraocular bleeding, haemorrhage at the access site requiring intervention, haematoma with
a diameter of at least 5 cm, a reduction in haemoglobin levels of at least 4 g/dL without an overt bleeding
source or at least 3 g/dL with such a source, reoperation for bleeding, or transfusion of a blood product
PLATO Major life-threatening
bleeding
Fatal bleeding, intracranial bleeding, intrapericardialbleeding with cardiac tamponade, hypovolemic shock or
severe hypotension due to bleeding and requiring pressors or surgery, a decline in haemoglobin level of
5.0 g per deciliter or more, or the need for transfusion of at least 4 units of red cells
Other major Bleeding that led to clinically significant disability (e.g. intraocular bleeding with permanent vision loss) or
bleeding either associated with a drop in the haemoglobin level of at least 3.0 g per deciliter but less than
5.0 g per deciliter or requiring transfusion of 2 to 3 units of red cells
Minor Any bleeding requiring medical intervention but not meeting the criteria for major bleeding
GRACE Severe Bleeding requiring transfusion of ≥2 units of packed red blood cells; bleeding resulting in a ≥10% decrease
in haematocrit or death; or intracranial/subdural bleeding
STEEPLE Major Fatal bleeding; retroperitoneal, intracranial, or intraocular bleeding; bleeding that causes haemodynamic
compromise requiring specific treatment; bleeding that requires intervention (surgical or endoscopic) or
decompression of a closed space to stop or control the event; clinically overt bleeding, requiring any
transfusion of ≥1 unit of packed red cells or whole blood; clinically overt bleeding, causing a decrease in
haemoglobin of ≥3 g/dL (or, if haemoglobin level not available, a decrease in haematocrit of ≥10%)
ISTH Major Fatal bleeding or symptomatic bleeding in a critical area or organ (e.g. intracranial, intraspinal, intraocular,
retroperitoneal, intraarticular, pericardial, or intramuscular), or a bleeding causing haemoglobin decrease
of .2 g/dL, or requiring .2 U transfusion
P.G. Steg et al.Page 2 of 14
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complications
13
(Table 2). The clinical relevance of the milder
bleeding events may vary depending on the clinical setting: it may
be minimal when considering life-saving thrombolytic treatment
in acute myocardial infarction but important for outpatients
beyond the first few months after an ACS.
Defining bleeding is particularly difficult in specific settings such
as during the peri-operative period for coronary artery bypass
grafting (CABG) surgery where some degree of blood loss and
transfusion is extremely common. Because patients undergoing
bypass surgery are at high risk of bleeding, CABG-related bleeding
may account for a disproportionate number of bleeding events in
ACS trials even though only approximately 10% of ACS patients
ultimately undergo surgery. Excluding these CABG-related bleeds
from safety outcomes in clinical trials violates the intention-to-treat
analysis principle, while including them may dilute differences in
bleeding risk. Such different approaches were recently used in
the TRITON-TIMI38 and PLATO trials.
Because there are multiple definitions and multiple iterations of
a given definition, it is often difficult for clinicians to know the clini-
cal relevance of the bleeding risk associated with new therapies.
The lack of a common definition also hampers comparison
across studies. There have therefore been calls for use of
common data elements and for a consensus grading of bleeding
events severity.
4,14
Recently, a consensus effort by academics, research organiz-
ations, industry, and regulator representatives resulted in the
Bleeding Academic Research Consortium (BARC) standardized
bleeding definitions for cardiovascular clinical trials.
15
In developing
these definitions, consideration was given to the need to address
some of the limitations of some of the classical historical defi-
nitions, to capture bleeding events which are meaningful to
patients and impact clinical outcomes, while remaining practical
and easy to implement. These broadly applicable definitions
attempt to describe both CABG-related, non-CABG-related, and
total bleeding rates, in a hierarchical manner characterizing severity
using an objective graded numerical system nomenclature
(Table 3). These definitions are based on consensus rather than
data driven. Yet, because of the importance of a unified definition,
it will be important that they be validated against existing and
future data sets in order to be embraced by all the clinical trial
community and become routinely used in clinical practice.
Epidemiology of bleeding in acute
coronary syndrome
Emerging evidence of a strong and potentially modifiable associ-
ation of bleeding with subsequent adverse outcomes
10,16,17
has
focused the attention of clinicians on the determinants of bleeding
and methods to avoid bleeding in patients with an ACS.
4
To this
purpose, recommended data collection and reporting of the inci-
dence of bleeding in ACS patients are summarized in Table 4.
Most information on the epidemiology of bleeding in ACS
patients comes from randomized controlled trials (RCTs) evaluat-
ing the efficacy and safety of the different antithrombotic drugs.
However, RCTs underestimate the frequency of bleeding for
various reasons (Table 5), and it has been pointed-out that
RCT-eligible patients outside of the context of trials (i.e. patients
from routine practice who would fulfil the selection criteria for
RCTs) have worse outcomes than participants in RCTs.
18
Interpretation of bleeding data from RCTs is further complicated
by differences across studies in definitions of bleeding, the increas-
ing use of combinations of antithrombotic drugs and PCIs, both of
which increase the risk of bleeding, and differences in the manage-
ment strategies for bleeding, for example the use of red blood cell
transfusions, which is often used to define the occurrence and
severity of bleeding.
4,5,7
Compared with RCTs, registry studies usually include a more
representative sample of patients with ACS, and are therefore
more likely to provide reliable estimates of the ‘real-world’ fre-
quency of bleeding. The interpretation of bleeding data from reg-
istry studies is, however, also limited by changes over time in
antithrombotic drugs and PCIs, and geographical variability in the
management of bleeding, e.g. differences in the use of red blood
cell transfusions in North America and Europe. Furthermore, regis-
tries may underestimate the frequency of bleeding because data
collection is often retrospective and relies on data extraction
from clinical records.
Despite more aggressive interventional therapy and more
aggressive anti-thrombotic therapy over recent years, a decline in
the rate of bleeding has been recently reported in data from the
GRACE registry.
19
Although the causes for this are unclear, clinical
practice factors may have influenced this decline, which is not
accounted for by the risk status of the patients.
...............................................................................................................................................................................
Table 2 Bleed score classification
13
Severity Criteria Points
Superficial Easy bruising, bleeding from small cuts, petechia, ecchymosis 1
Internal Haematoma, epistaxis, blood loss from mouth, vagina, melena, eye bleed, haematuria, haematemesis 3
Alarming Transfusion needed, intracranial, life threatening 6
The minimal BleedScore is 0, each event is added. Points are accrued on an open-ended scale. Bleeding complications are monitored continuously throughout a given trial. For
reporting purposes, the 30 contiguous days prior to a given patient assessment (e.g. during a trial study-visit) constitute the index-month for reporting the BleedScore. A
subscript-index (‘S’, ‘I’ or ‘A’) is given at the end of the score, reflecting each category from which points were accrued.
Example for scores: 1S, 0I, 0A; 2S, 3I, 6A; etc.
For simplified statistical assessment, e.g. in large-scale trials, points can also be combined into a pooled total BleedScore (e.g. in the examples above: pooled BleedScore 1 +0+0¼
1; 2+3+6¼11 etc.)
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Specific groups at risk of bleeding
Despite the variations in incidence and definition of bleeding
across studies, older age, female sex, lower body weight, use of
invasive procedures, and renal insufficiency have been consistently
found to be powerful predictors of bleeding complications in ACS
and PCI (Figure 1). Increasing age is a strong risk factor for bleeding:
in the GRACE registry encompassing the whole spectrum of ACS,
the adjusted odds of having a major haemorrhage prior to dis-
charge increased by about 30% per decade of age [odds ratio
(OR) 1.28, 95% CI 1.21–1.37].
10
An hypothetical explanation is
that with age, collagen and amyloid deposits in the ageing arterial
tunica media may cause brittle, leaky vessels that are less inclined
to constrict and are more prone to bleed. Women with ACS also
tend to have a higher risk of bleeding than men: within the GRACE
registry, women had a 43% higher likelihood of developing major
bleeds in-hospital compared with men (adjusted OR 1.43, 95%
CI 1.23–1.66).
10
This increased risk presumably stems from
smaller body and vessel size, reduced creatinine clearance (for a
given weight and serum creatinine), higher prevalence of comor-
bidities, higher risk of drug overdosing,
20
and, perhaps, differences
in pharmacological response to antithrombotics compared with
men.
21
Renal function also plays an important role in bleeding
risk: in contemporary ACS registries, the estimated risk of
in-hospital major bleeds increases by approximately 50% in
patients with renal insufficiency (OR 1.48, 95% CI 1.19– 1.84).
10
In a post hoc analysis of over 34 000 patients enrolled in
NSTE-ACS trials and followed for up to 12 months, the adjusted
OR for major bleeds was 1.4 (95% CI 1.3–16) for each 1.13 mg/
dL (or 100 mmol/L) rise in baseline creatinine; indeed, serum crea-
tinine and age were the two most powerful predictors of bleed-
ing.
16
Patients with renal failure are more susceptible to excess
dosing of antithrombotic drugs but also typically have more
...............................................................................................................................................................................
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Table 3 BARC definition for bleeding
15
Type 0: No bleeding
Type 1: Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health
care professional
Type 2: Any overt, actionable sign of haemorrhage (e.g. more bleeding than would be expected for a clinical circumstance; including bleeding found by
imaging alone) that does not fit the criteria for Types 3, 4, or 5, but does meet at least one of the following criteria: (1) requiring non-surgical, medical
intervention by a health care professional, (2) leading to hospitalization or increased level of care, (3) prompting evaluation
Type 3
Type 3a
Overt bleeding plus haemoglobin drop of 3 to ,5*g/dL (provided haemoglobin drop is related to bleed)
Any transfusion with overt bleeding
Type 3b
Overt bleeding plus haemoglobin drop ≥5*g/dL ( provided haemoglobin drop is related to bleed)
Cardiac tamponade
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/haemorrhoid)
Bleeding requiring intravenous vasoactive drugs
Type 3c
Intracranial haemorrhage (does not include microbleeds or haemorrhagic transformation; does include intraspinal)
Subcategories; confirmed by autopsy or imaging or LP
Intra-ocular bleed compromising vision
Type 4: CABG-related bleeding
Perioperative intracranial bleeding within 48 h
Reoperation following closure of sternotomy for the purpose of controlling bleeding
Transfusion of ≥5 units of whole blood or packed red blood cells within a 48 period**
Chest tube output ≥2 L within a 24 h period
If a CABG-related bleed is not adjudicated as at least a Type 3 severity event, it will be classified as ‘not a bleeding event’
Type 5: fatal bleeding
Type 5a
Probable fatal bleeding: no autopsy or imaging confirmation, but clinically suspicious
Type 5b
Definite fatal bleeding: overt bleeding or autopsy or imaging confirmation
Obs: Platelet transfusions should be recorded and reported, but are not included in these definitions until further information is obtained about the relationship to outcomes.
*Corrected for transfusion (1 unit PRBC or 1 unit whole blood ¼1 g/dL Hgb). **Only allogeneic transfusions are considered transfusions for BARC Type 4 bleeding. Cell saver
products will not be counted.
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diffuse and advanced arterial disease and therefore may be prone
to higher risks of both thrombosis and bleeding.
In addition to these clinical factors, genetic factors also predis-
pose to bleeding: among patients initiating warfarin therapy, car-
riers of the cytochrome P450 (CYP) 2C9 gene variants *2 and
*3 and of the C1173T variant of vitamin K epoxide reductase
complex subunit 1 require lower doses and develop more often
an INR .4 compared with non-carriers.
22
Likewise, in clopidogrel-
treated patients, the gain-function variant CYP2C19*17 resulting in
higher active clopidogrel metabolite levels and increased platelet
inhibition has been linked to an increase in the incidence of bleed-
ing without improved efficacy.
23
Prognostic implications of
bleeding in acute coronary
syndrome
The clinical impact of bleeding has long been downplayed due to
the availability of blood transfusions and haemostatic agents, with
bleeding often merely regarded as an unpleasant event, increasing
the length of hospital stay and costs, but not clearly impacting sur-
vival. It was only recently recognized that major bleeding was
associated with a subsequent increase in late mortality, potentially
negating the long-term benefits of ACS treatment.
10,24 –26
Compared with patients without bleeding, patients who experi-
ence bleeding are more likely to die not only early in-hospital but
also late after discharge.
26 –28
One possibility to explain the
relationship of bleeding with adverse outcomes in routine practice
is that recognized predictors of bleeding have much overlap with
predictors of ischaemic events; bleeding acting as a marker for
increased ischaemic risk as well as contributing to death in some
cases. A second possibility is that bleeding has directly harmful con-
sequences and also set in motion a number of adaptive changes, in
turn themselves leading to an adverse outcome. Consequences of
bleeding include hypotension, anaemia, and reduction in oxygen
delivery (Figure 2). Experimental data suggest that a haemoglobin
level down to 7 g/dL is tolerated without myocardial ischaemia if
there is no obstructive coronary artery disease (CAD).
29
Anaemia per se is associated with an increased risk of adverse
...............................................................................................................................................................................
Table 5 Reasons why randomized trials may underestimate the ‘real-world’ incidence of clinically important bleeding
in acute coronary syndrome
Characteristic Reason
Study population Highly selected patients at low risk of bleeding
Timing of recruitment Convenience sampling; recruitment may be delayed until hours or days after presentation with acute coronary syndrome
Interventions Standardized management protocol are rigorously applied in randomized trials but are not equally applied in everyday clinical
practice
Bleeding outcome Clinically important bleeding may not be captured by the definitions used for major and minor bleeding
...............................................................................................................................................................................
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Table 4 Recommended data collection and reporting of the incidence, severity, management, and sequelae of bleeding
in acute coronary syndrome
Category Recommended data point
Timing Timing of bleeding in relation to presentation
Location Organ system involved
Precipitating or contributing
therapies
Antithrombotic and invasive therapies and the intensity of treatment where relevant (e.g. dose, INR, aPTT) immediately
prior to or at time of bleed
Presentation Whether bleed was symptomatic or not
Severity Nadir haemoglobin (or haematocrit)
Number of units of red blood cells transfused
Need for inotropes
Need for surgical intervention
Need for hospitalization
Need for medical intervention
Sequelae/outcomes
a
Fatal bleeding
Modification of antithrombotic therapy (permanently or temporary discontinuation)
Use of anti-fibrinolytic and general haemostatic agents (e.g. recombinant factor VIIa)
Myocardial infarction
Stroke
a
Patients should be followed for a minimum of 6 months after an episode of bleeding.
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outcomes in patients with ACS, or undergoing coronary revascu-
larization.
30 –32
However, many patients with anaemia actually pre-
sented with anaemia prior to receiving any antithrombotic therapy
and without overt bleeding. In these patients, pre-existing anaemia
may exacerbate the consequences of subsequent bleeding, and
certainly increases the probability of transfusion.
Discontinuation of antithrombotic therapy to minimize bleeding is
an important triggerof ACS.
33,34
It may re-exacerbate the thrombotic
risk allowing the accretion of new thrombus material. In the face of
bleeding, no general guideline can be given. Clinicians need to
weigh the respective risks related to ongoing bleeding, dose
reduction, or temporary discontinuation of antithrombotics, when-
ever possible, with rapid resumption of the initial antithrombotic
therapy, depending on the half life and reversibility of the effect and
the possibility to treat bleeding (e.g. compressible vs. non-
compressible bleeding site). Antithrombotic therapy should be,
however, discontinued if bleeding leads to hypotension or if bleeding
is life-threatening and uncontrolled. This should be followed by
haemodynamic support with fluid repletion and vasopressor
therapy as necessary. All of these actions, however, place the
patient at increased risk of recurrent ischaemia and infarction.
Transfusion of whole blood or packed red blood cells might
have appeared the simple and ultimate solution to manage major
bleeding, as it rapidly compensates for the volume loss associated
with the bleeding event, and as such is indicated when bleeding is
associated with haemodynamic instability or shock. However,
when bleeding is less severe and haemodynamic conditions
remain stable, the effect of transfusions on mortality is at best
neutral. Even in patients with cardiovascular diseases or in the
elderly, transfusion have no positive impact on outcome.
29,35
Fur-
thermore, despite major bleeding with the loss of .5 g/dL haemo-
globin, blood transfusion is associated with increased mortality, and
blood loss down to a nadir haematocrit as low as 25% may be well
tolerated.
36
There are many potential mechanisms for the
Figure 1 Predictors of bleeding in acute coronary syndrome. Adapted from Moscucci et al., GRACE.
9
Referent groups male sex: UFH for
LMWH only, both LMWH and UFH, and neither LMWH nor UFH, neither thrombolytics nor GP IIb/IIIa blockers for thrombolytics only,
GP IIb/IIIa blockers only, and both thrombolytics and GP IIb/IIIa blockers; no for other variables. Hosmer– Lemeshow goodness-of-fit test
P-value ¼0.59, C-statistic ¼0.75. GP, glycoprotein; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
Figure 2 Schematic representations of the hypothetical mech-
anisms linking bleeding and mortality.
P.G. Steg et al.Page 6 of 14
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detrimental effects of transfusions, including platelet activation and
aggregation, impaired oxygen, and nitric oxide delivery capabilities
(Figure 3).
37
As a matter of fact, in general, restrictive transfusion
strategies are associated with trends towards decreased mortality,
myocardial infarction, and heart failure.
37
Therefore, transfusion
may increase rather than decrease the risk of adverse events in
patients with ACS.
38
Likewise, the common
39
liberal use of
blood transfusion to maintain predefined haemoglobin levels in
CAD patients without overt bleeding and with haematocrit
.25% or haemoglobin .8 g/dL is not recommended.
Bleeding in percutaneous coronary
intervention
In patients undergoing PCI, approximately half of the bleeding
events occur at the arterial access site, and may range from clini-
cally unimportant subcutaneous access site haematoma to fatal ret-
roperitoneal bleeding.
40
The deleterious impact of access and
non-access site bleeding on outcomes is established but the
impact on mortality appears greater for non-access site bleeding.
5
One should also consider remote bleeding complications, unre-
lated to the procedure itself but caused by the protracted com-
bined antiplatelet therapy required after stent placement.
Bleeding rates in patients undergoing PCI vary according to defi-
nition and to the clinical setting for PCI,
38,40
with lowest rates in
elective PCI
41
and the highest rates in primary PCI for STEMI.
25
Importantly, the absolute increase in mortality caused by major
bleeding in ACS is substantial, in the order of 11% (95% CI
8–14) corresponding to a number of patients ‘needed to harm’
of only 9.1 (95% CI 7.1–12.5), deserving careful attention from
clinicians.
42
Furthermore major bleeding is also associated with
increased risk of ischaemic events.
Although radial access for angiography and PCI is associated
with near abolition of access site bleeding,
43,44
some infrequent
complications persist, which may range from local superficial hae-
matomas in the forearm, found in less than 5% of cases, to excep-
tional compartment syndrome, found in ,0.01% of cases. Use of
access site closure devices does not appear to have a major impact
in the prevention of severe bleeding.
45
Although clearly not the sole consideration, prevention of
bleeding is important when selecting antithrombotic strategies
for PCI. There are differences in the risk of bleeding according
to the type and dosing of antithrombotic therapies used for
PCI.
26,41,46 –49
Given the impact of drug overdosing on bleeding
and its interaction with age, sex, and renal function,
20,21
attention
should be devoted to appropriate dosing, particularly in patients
at high risk for bleeding, identified readily on the basis of these
simple clinical baseline characteristics
10,19,20,47
or using risk
scores.
50
Avoidance of bleeding in acute
coronary syndrome and
percutaneous coronary
intervention
The role of overdosing
Overdosing is a frequent situation associated with established
increased major bleeding risk and in-hospital death.
20,21
Using
the minimal effective dose and adjusting the dose, when appropri-
ate, to body weight, age, and to renal function are sensible steps to
minimize the risk of bleeding.
Fondaparinux, low-molecular-weight heparins (LMWH), hirudin,
argatroban, bivalirudin, and GP IIb/IIIa blocker are largely cleared
by the kidneys, and should therefore not be used or need to be
down-titrated in patients with severe renal failure, defined as a
creatinine clearance ,30 mL/min.
20,21
Unfractionated heparin
remains the anticoagulant of choice in this particular situation,
but does not totally protect against bleeding complications. With
worsening renal function, there is a gradual increase in the risk
of bleeding with UFH, similar to that seen with LMWH.
51
Unfractionated heparin, LMWH, intravenous direct thrombin
inhibitors, TNK-tPA, and GP IIb/IIIa blockers all require careful
weight-adjusted dosing.
28,46,47,51,52
The use of high loading and
maintenance doses of clopidogrel to speed up its efficacy and over-
come high residual-on treatment platelet reactivity, especially in
the setting of PCI, may be beneficial in terms of clinical outcomes,
although in the CURRENT/OASIS 7 trial this was only seen in
patients going on to PCI,
53
but not when the trial was analysed
by intention-to-treat
54
and was achieved at the expense of
increased major bleeding.
Use for the shortest possible duration
In determining the duration of antithrombotic therapy, it is impor-
tant always to balance the bleeding-related risks with the antith-
rombotic benefits, and therefore adopt the shortest possible
course of therapy. As an example, dual therapy with aspirin and
clopidogrel is recommended for 1 month after bare metal stenting
in stable patients, and for 6 up to 12 months after an ACS (regard-
less of stenting) and after implantation of drug eluting stents
(regardless of clinical diagnosis). Continuation of dual antiplatelet
therapy beyond these intervals should be considered an exception
rather than the rule. So far, there is a single randomized study
Figure 3 Potential mechanisms of the detrimental effect of
blood transfusion.
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showing no hazard of clopidogrel discontinuation 1 year after
drug-eluting stent implantation.
55
There are currently 11 random-
ized trials ongoing comparing various duration of dual antiplatelet
therapy in this setting (Table 6).
Choice of drugs
Antithrombotic agents shown to produce less bleeding while main-
taining anti-ischaemic efficacy in randomized trials should be pre-
ferred, particularly for those for whom bleeding reduction was
associated with reduced mortality or improved clinical outcomes.
This is the case of fondaparinux against enoxaparin in the
medical management of patients with NSTE-ACS
26
and of bivalir-
udin vs. UFH+GPIIb/IIIa blockers in primary PCI for ST-segment
elevation myocardial infarction.
25
Agents which lower bleeding
rates while achieving non-inferior efficacy are also of interest,
although consideration of the individual patient risk profile for
bleeding and MI becomes an important factor in the decision-
making process. This is the case for bivalirudin vs. UFH +GpIIb/
IIIa blockers in NSTE-ACS
28,56
and, possibly, of enoxaparin vs.
UFH in patients undergoing elective or primary angioplasty.
41,57
Reducing gastrointestinal bleeding
The risk of gastrointestinal haemorrhage increases two- to three-
fold even with low-dose aspirin monotherapy compared with
placebo, and all doses of aspirin are associated with an increased
risk of gastrointestinal bleeding. The risk of aspirin-related ulcer
complications is significantly increased in patients aged more than
60 years, patients with serious comorbidities, concomitant use of
non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticos-
teroids, anticoagulants, or other antiplatelet agents. Overall, there is
no evidence of decreased efficacy, but clear evidence of increased
safety with lower doses of aspirin.
54
Proton-pump inhibitors
display a high capacity to reduce recurrent gastrointestinal bleeding
in patients at high risk for gastrointestinal side effects under chronic
aspirin therapy, although they are not effective in preventing lower
gastro-intestinal bleeding.
58
Adding a proton-pump inhibitor to
reduce gastrointestinal bleeding events in patients at high risk of gas-
trointestinal toxicity who receive long-term treatment with
low-dose aspirin is recommended.
59
On the other hand, there is a
pharmacologic interaction between omeprazole and clopidogrel,
60
which is some observational cohorts appeared to be associated
with higher cardiovascular event rates. However, the jury is still
out regarding the clinical significance of this interaction, which did
...............................................................................................................................................................................
Table 6 Ongoing randomized clinical trials comparing various durations of dual antiplatelet therapy after placement of
drug-eluting stents
Study Patients (n) Randomization Primary outcome measure Secondary outcomes
ISAR-SAFE,
NCT00661206
PCI-DES (6 000) 6 vs. 12 months 15 months: death/MI/stroke/TIMI
major bleed
Individual component outcomes
ISAR-CAUTION,
NCT00640679
PCI-DES (3000) 12 vs. tapered within 4
weeks after 12 months
3 months: CV death, non-fatal MI or ST,
stroke, major bleeding or
rehospitalization for ACS
The individual components of the
primary outcome. All cause
mortality
ARCTIC,
NCT00827411
Elective PCI–
DES (2466)
12 vs. 18–24 months 12 months: composite endpoint of
death, M, stroke, Urgent
revascularization, ST
Individual component outcomes
OPTIDUAL,
NCT00822536
PCI-DES
(n¼1966)
12 vs. 36–48 months 3 years: death, non-fatal myocardial
infarction, non-fatal stroke, and
severe bleeding
Individual component outcomes,
stent thrombosis (ARC), target
vessel revascularization
DAPT Study,
NCT00977938
DES/BMS– PCI
(n¼20645)
12 vs. 30 months 30 months: (1) death/MI/stroke at 33
months: (2) Def/prob ST at 33
months
GUSTO bleeding
ITALIC,
NCT00780156
PCI-DES
n¼3200)
6 vs. 36 months in aspirin
good responders
12 months: death, MI urgent revasc,
stroke requiring a new
hospitalisation and major bleedings
Individual component outcomes, at
24 and 36 months and bleeding
complications
OPTIMIZE,
NCT01113372
PCI-ZES
(n¼3120
non-STEMI)
3 vs. 12 months 1-year death/MI/stroke/ TIMI major
bleed
ARC stent thrombosis
CYPRESS-phase II,
NCT00954707
PCI-SES
(n¼2500)
12 vs. 30 months Death/MI/stroke at 12 – 33months Stent thrombosis; bleeding
TAXUS study,
NCT00997503
PCI-PES
(n¼4200)
12 vs. 30 months Death/MI at 12 months Stent thrombosis
EASTS,
NCT01233167
PCI-SES (n¼?) 12 vs. 24 months vs.
tapered
Death/MI/TVR Multiple individual EP
SCORE,
NCT00781573
PCI-DES (n¼?) 12 vs. 24 months Death/MI at 12 months Death/MI/stroke/repeat revasc/
bleeding at 12 months
DES, drug-eluting stent; ZES, zotarolimus-eluting stent; SES, sirolimus-eluting stent.
P.G. Steg et al.Page 8 of 14
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not appear to impact clinical outcomes in one prospective, albeit
somewhat underpowered, randomized trial
61
or in other large
observational cohorts.
62 –64
Whether proton pump inhibitors
should be routinely added to the already long list of medications
needed after an ACS or PCI requires testing, given the implications
in terms of cost, adherence to polypharmacy, and cost-effectiveness,
and is not at the moment recommended. Instead, a recent consen-
sus document on the concomitant use of proton pump inhibitors
and thienopyridines highlights that proton pump inhibitors are
appropriate in patients with risk factors for gastrointestinal bleeding
who require antiplatelet therapy,
65
such as patients with prior
history of upper gastro-intestinal tract bleeding, advanced age; con-
comitant use of warfarin, steroids, or NSAIDs; or H. pylori infection.
Preventing access site bleeding
Numerous devices have been developed to obtain efficient arterial
closure immediately at the end of a PCI procedure performed with
the femoral approach, but have failed to abolish major access site
bleeds or improve clinical outcomes.
45
Consistent results indicate
that a reduced arterial sheath size, timely sheath removal, and the
use of radial (instead of femoral) artery access for PCI are associated
with a frank reduction in peri-PCI bleeding rates. Using a radial
approach, as opposed to femoral access for angiography and PCI
appears remarkably effective in preventing access site bleeding
43,44
:
pooled results from 17 randomized studies indicate a 78% reduction
in entry site complications when a radial approach is used, with a
number need to treat of only 39 patients.
43
Whether using radial
access for PCI in ACS patients can improve clinical outcomes is
being tested in the 7000 patient RIVAL randomized trial.
66
In the
interim, a large observational database analysis has suggested that in
patients at higher risk for bleeding, use of vascular closure devices
and bivalirudin for PCI were associated with lower bleeding rates.
67
Patients on chronic oral anticoagulation
Given the concerns with increased bleeding risk in patients receiving
protracted triple antithrombotic therapy with oral anticoagulants
(atrial fibrillation, venous thrombosis, pulmonary embolism, mechan-
ical prosthetic valves),
68
aspirin, and thienopyridines,it makes sense to
minimize the overlap between these agents, and therefore to prefer
bare metal stents over drug-eluting stents in order to allow safeearly
discontinuation of clopidogrel. The selection of a post-PCI antithrom-
botic strategy in this context should probably be based on individual
patient characteristics, as retrospective analyses suggest that triple
therapy provides the best benefit-risk ratio, provided that clopidogrel
co-treatment is kept as short as possible.
63
In general, if the patient is
at high risk of thromboembolic events requiring oral anticoagulants
(e.g. because of a prosthetic mitral valve, recent venous thrombosis
or pulmonary embolism, or atrial fibrillation with a CHADS
2
score.1), triple oral antithrombotic therapy (aspirin +
clopidogrel +oral anticoagulants) should be used until clopidogrel
can be safely discontinued. Once the risk of stent thrombosis is
lower, consideration should be given to oral anticoagulants alone,
69
although contemporary studies on this important topic are lacking.
This is, in fact, an incentive to use bare metal stents during PCI pro-
cedures in these patients in order to discontinue clopidogrel after 4
weeks. In patients with a lower thromboembolic risk in whom oral
anticoagulation is optional (e.g. atrial fibrillation with CHADS
2
score 0– 1)—especially if they have an increased bleeding risk (e.g.
age .75 years, severe renal dysfunction, recent gastrointestinal
bleeding, prior stroke, uncontrolled hypertension)—physicians may
consider using dual antiplatelet therapy for several weeks before
resuming oral anticoagulants and discontinuing one oral antiplatelet
agent or maintaining dual antiplatelet therapy in the long term as it
has a better efficacy profile than aspirin alone at least in patients
with atrial fibrillation considered unsuitable for vitamin K antagonists
(Figure 3).
69
For long-term use, after the need of clopidogrel has
waned, we concur with the recent ESC Atrial Fibrillation guidelines
in recommending VKA alone rather than the combination of
VKA +aspirin.
69,70
For patients who develop ACS while being on
chronic oral anticoagulation, adding antiplatelet therapy to oral antic-
oagulation should be considered, but the optimal duration of ‘triple’
antithrombotic therapy in these patients is unknown and should
probably be minimized, particularly in patients who do not undergo
placement of a stent, in order to minimize bleeding risks.
Management of bleeding in acute
coronary syndrome
As indicated by the ESC Guidelines,
71
bleeding can be managed with
simple means. Sometimes antithrombotic therapy must be partially
or completely discontinued and even antagonized by specific drugs
and measures. In patients who have undergone stenting and in
whom dual antiplatelet therapy is indicated, withholding one or
both antiplatelet agents should always be considered putting the
patient at substantial risk of stent thrombosis; therefore, the benefits
of treatment interruption need to be weighed against the risks of
stent thrombosis and treatment interruption should always be con-
sidered as a temporary measure. Guidelines for the perioperative
management of antiplatelet agents
72
provide a useful algorithm
(Table 7). As often as possible, oral antiplatelet therapy must be
restarted after the bleeding event is resolved.
General management of bleeding
Patients with ACS may experience bleeding due to procedures or
as a side effect of antithrombotic treatment. Minor bleeding usually
does not need medical attention during the acute phase. There is,
however, evidence that, after discharge, minor or nuisance bleed-
ing may lead patients to discontinue antiplatelet therapy, which
may lead to recurrent ischaemic events.
12,73 –75
Patients experien-
cing significant or major bleeding during an ACS should be closely
monitored, preferably in an intensive or coronary care unit, and
transfusions should be considered in haemodynamically unstable
patients (including patients with ongoing severe bleeding) and
should not be underdosed. Antithrombotic treatment interruption
may be associated with recurrent ischaemic events. Proton pump
inhibitors should be the preferred agents for the therapy and pro-
phylaxis of ASA-associated gastro-intestinal injury.
59,65,75
This and
additional local endoscopic treatment may control gastrointestinal
bleeding and avoid interruption of antiplatelet therapy, a decision
to be made on a strictly individual basis.
59
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Management of bleeding according to
specific situations
The management of bleeding complications in special situations
can be summarized as follows:
†Minor bleeding should preferably be managed without interrup-
tion of active treatments (grade I, level of evidence C).
†Major bleeding requires interruption and/or neutralization of
both anticoagulant and antiplatelet therapy, unless bleeding
can be adequately controlled by specific haemostatic interven-
tions (grade I, level of evidence C).
†Blood transfusions may have deleterious effects on outcome
and should therefore be considered individually, but withheld
in haemodynamically stable patients without overt bleeding
with haematocrit .25% or haemoglobin level .8 g/dL (grade I,
level of evidence C).
Clinical research implications
Measuring and reporting bleeding in trials
With the use of invasive methods for diagnosis and treatment, par-
ticularly PCI with femoral arterial access and with the increasing
antithrombotic armamentarium used to avoid thrombotic compli-
cations, the importance of bleeding complications as a mechanism
contributing to mortality has recently emerged.
In addition to the mere reporting of bleeding according to
accepted definitions, risk factors for major bleeding in patients
with ACS should be collected and analysed to identify subgroups
of patients that need special care with regard to antithrombotic
treatment in ACS, and current guidelines should take them into
consideration. To build-up a base of evidence for the handling of
this balance in clinical practice, definitions of bleeding should be
internationally uniform and relevant to the clinical situation, for
comparison across geographic regions, ethnicities, and other rel-
evant population differences, looking for valid risk factors and
optimal treatment of the delicate haemostatic/thrombotic
balance in various phases of the disease. Bleeding should be
reported using more than one bleeding scale,
14
one of which
should be the BARC bleeding definition.
15
Bleeding as an outcome measure in trials
Bleeding is an important predefined endpoint of all trials and regis-
tries of ACS and PCI, possibly of equal importance to events
related to ischaemia and thrombosis. Bleeding is significantly
associated with short-term mortality and, remarkably, a similar sig-
nificant difference between patients with major bleeding and those
without bleeding is noted also for thrombotic events such as myo-
cardial infarction and stroke.
16,17
In addition, interruption of antith-
rombotic therapy related to bleeding episodes is independently
associated with increased mortality.
73
These observations suggest
that increased haemostatic activation induced by the disease
state itself, interruption of antithrombotic therapy, and possibly
blood transfusions all contribute importantly to poor outcomes.
In addition to reporting bleeding events in ACS studies, the
‘number needed to harm’ (NNH) should be reported on to
balance the ‘number needed to treat’ (NNT) as an efficacy
measure. This should help analyse the contribution to efficacy
and safety by the various elements of the ‘therapeutic package’
as defined in Table 4. This table proposed an ‘ideal set’ of data per-
taining to antithrombotic drugs or bleeding to be collected in
future studies.
Bleeding as a subject for future research
Among the many remaining questions regarding bleeding, the most
pressing ones are the following:
†Is bleeding truly causal in subsequent mortality or is it merely a
marker of increased risk related to worse baseline
characteristics?
†To what extent and during what time frame is there an
increased risk of mortality related to bleeding?
†Is spontaneous bleeding different from bleeding induced by per-
cutaneous or surgical revascularization procedures?
.............................................................................................................................................................
...............................................................................................................................................................................
Table 7 Perioperative management of antiplatelet agents in patients with coronary stents: recommendations of a
French Anesthesiology and Intensive Care Task Force
72
Haemorrhagic risk of the invasive or surgical procedure (to be evaluated with the physician or the surgeon)
Major Intermediate Minor
Risk of stent thrombosis (to be evaluated with the cardiologist)
Major Postpone intervention 6 months to 1 year after stenting. If
impossible: Stop aspirin-clopidogrel 5 days or stop
aspirin-clopidogrel 10 days max and substitute
Postpone intervention 6 months to 1 year
after stenting. If impossible: maintain
aspirin stop clopidogrel 5 days
Maintain aspirin and
clopidogrel
Moderate Stop aspirin-clopidogrel 5 days or stop aspirin-clopidogrel
10 days max and substitute
Maintain aspirin stop clopidogrel 5 days Maintain aspirin and
clopidogrel or maintain
aspirin stop clopidogrel 5
days
Haemorrhagic risk: major: intervention cannot proceed on APA; moderate: intervention can proceed on ASA alone; minor: intervention can proceed on ASA and clopidogrel.
Risk of DES thrombosis: major: in place less than 6 months to 1 year or patient requiring ASA and clopidogrel or patient with risk factor; moderate: in place more than 6 months to
1 year.
APA, antiplatelet agents; ASA, aspirin.
P.G. Steg et al.Page 10 of 14
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†Which laboratory tests are clinically most suitable to assess the
haemostatic balance during the active treatment period?
†What are the basic changes in the haemostatic balance that take
place during the disease process in ACS and the various thera-
peutic interventions (including stopping of treatment and blood
transfusion), as explanation for the thromboembolic and bleed-
ing complications?
†Are there individual explanations, genetically or by coexisting
disease states, for the appearance of thromboembolic and/or
bleeding complications?
†Is transfusion really deleterious? What should be the optimal
transfusion strategy for patients with ACS?
†How should we address and treat anaemia in patients with ACS,
particularly in the perioperative period?
†Should more ‘tailored’ antithrombotic strategies, involving
shorter use of potent antithrombotic combinations and, poss-
ibly, reduced regimens of antithrombotic therapies, be used
for managing patients with ACS?
†In which ACS patient subsets should single, dual, triple, or quad-
ruple treatment (thrombolytic; single, dual, or triple antiplatelet;
anticoagulant) be administered? In which doses and for how
long, to avoid thromboembolic complications while minimizing
bleeding (using the NNT/NNH measures)?
Conclusions
Modern ACS management involves a mix of antithrombotic
therapy and invasive procedures. Guidelines for ACS management
give several agents their highest recommendation based on the
available trial data. However, all these therapies carry, to a
varying degree, a risk for bleeding. Bleeding complications are
important clinical events, associated with subsequent mortality.
Although reducing bleeding risk has become a clinical priority,
there remains gaps in knowledge regarding the incidence of bleed-
ing and the underlying mechanisms that explain the negative associ-
ations. Moreover, the varying definitions of bleeding used in clinical
studies to date have made it difficult to compare the safety of avail-
able agents. The recent Bleeding Academic Research Consortium
standardized approach to capturing bleeding information rep-
resents a first step in closing the knowledge gap, which will need
prospective validation in future studies. The recent confirmation
of a decline in the rate of bleeding together with large variations
in bleeding frequency from hospital to hospital also suggests that
change in local practice patterns impacts bleeding and calls for
reinforced attention from clinicians towards prevention and treat-
ment of bleeding.
Funding
This work was supported by the European Society of Cardiology and
by unrestricted grants from Sanofi-Aventis, Astra-Zeneca, The Medi-
cines Co and GlaxoSmithKline.
Conflict of interest: P.G.S.: Research grant (to institution): Servier;
Speaking or consulting: Astellas, AstraZeneca, Boehringer Ingelheim,
Bristol-Myers Squibb, Daiichi-Sankyo/Lilly, Eisai, GlaxoSmithKline,
Merck Sharp & Dohme, Novartis, Nycomed, sanofi-aventis, Sankyo,
Servier, The Medicines company; stockholding: Aterovax.
K.H.: speaker: AstraZeneca, Bayer, Boerhinger-Ingelheim, Eli-Lilly/
daiichi Sankyo, Pfizer, sanofi-aventis, The Medicines Company.
F.A.: research funding: Merck-Sharpe Dohme, speaker: AstraZeneca,
Bayer, Daiichi-Sankyo, Pfizer; consultant: Bayer, Bristol-Myers Squibb,
Boehringer-Ingelheim, Daiichi-Sankyo/Eli Lilly, Pfizer.
H.A.: lecture honorariums from Nycomed Pharma, Eli Lilly and
Boehringer Ingelheim.
D.A.: has a patent on the Bleed Score.
L.B.: speaker: AstraZeneca, Boehringer-Ingelheim, Eli Lilly; consult-
ant: Astrazeneca, Esteve.
J.-P.B.: consulting: sanofi-aventis, AstraZeneca, Endotis Pharma; stock
ownership GlaxoSmithKline, Lilly, sanofi-aventis; speaking: AstraZe-
neca, GlaxoSmithKline, Lilly, sanofi-aventis, Servier.
R.C.: speaking or consulting honoraria: Bayer, Boehringer Ingelheim,
Bristol-Myers Squibb, Sanofi-Aventis, Daiichi-Sankyo, Eli Lilly, AstraZe-
neca, Pfizer.
J.E.: honoraria and/or research support from Bristol-Myers Squibb,
Bayer, Daiichi Sankyo/Eli-Lilly, AstraZeneca, sanofi-aventis, Novartis,
Johnson and Johnson, Leo, Merck, Portola, Pfizer.
M.H.: research: Daiichi-Sankyo/Lilly, GlaxoSmithKline, The Medi-
cines Company; consultant/speaker: Biotronik, Cordis, Medtronic,
Terumo, The Medicines Company.
G.H.: Research: Boston Scientific, Cordis, Medtronic, Terumo, Bio-
tronik. Consulting: Procter & Gamble, Boehringer-Ingelheim, Speaking:
Ipsen, Servier, Boehringer-Ingelheim.
K.A.A.F.: research grant: Biosite, Bristol-Myers Squibb, Blue Cross
Blue Shield of Michigan, Hewlett Foundation, Mardigian Fund, Pfizer,
sanofi-aventis, Varbedian Fund; consultant: NIH NHLBI, Pfizer,
sanofi-aventis, Robert Wood Johnson Foundation.
S.D.K.: speaking: AstraZeneca, Eli Lilly, Daichii-Sankyo, Merck, The
Medicines Company.
S.V.R.: consultant: sanofi-aventis, BMS, Daiichi Sankyo Lilly, The
Medicines Company, Astra Zeneca, Terumo Medical; research
funding—Novartis, Cordis, Ikaria.
F.W.A.V.: Educational and research grants from Bayer AG, Roche, Eli
Lilly and Boehringer Ingelheim, and honoraria for consultancies from
Daiichi-Sankyo, Eli Lilly, Merck, The Medicines Company and Bayer
AG.
P.W.: speaker: Eli Lilly, Boehringer-Ingelheim, sanofi-aventis, Medtro-
nic, Abbott, Boston Scientific.
Uwe Zeymer: nothing to disclose.
J.-P.C.: research: BristolMyers Squibb, sanofi-aventis, EliLilly, Guerbet
Medical, Medtronic, Boston Scientific, Cordis, Stago, Fondation de
France, INSERM, Fe
´de
´ration de Cardiologie, Socie
´te
´Franc¸aise de Car-
diologie. Speaking: BristolMyers Squibb, sanofi-aventis, EliLilly.
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